Is hypospadias a spectrum of different diseases? MAMLD1 gen : A new candidate gene for hypospadias

Las hipospadias resultan de un arresto en el desarrollo normal de la uretra, creando un meato ectópico proximal en la cara ventral del pene. Estudios moleculares y un mejor conocimiento de la embriogénesis del tubérculo genital demuestran una compleja interacción de genes, hormonas y el ambiente con el desarrollo de hipospadias. Es posible que esta entidad sea la expresión fenotípica común de varias enfermedades diferentes. Recientemente se describió un nuevo gen candidato en el desarrollo de hipospadias llamado MAMLD1, involucrado en la producción normal de testosterona durante la embriogénesis.Q4Artículo de revisión155-160Hypospadias is the result of an abnormal development of the urethra causing an ectopic and more proximal placement of the meatus in the ventral side of the penis. Recent molecular studies, and a better understanding of the normal development of the genital tubercle, have demonstrated a complex interaction between genes, hormones and the environment with the development of hypospadias. It is possible that hypospadias is the phenotypic expression of different diseases. Recently a new candidate gene for hypospadias has been discovered, called MAMLD1, which is involved in the normal production of testosterone during foetal development

Long-term follow-up after traditional versus modified perineal approach in the management of female epispadias

Q2e1–497.e5Objective Isolated female epispadias (IFE) is a rare congenital anomaly. The defect extends to the bladder neck, which is usually incompetent. The traditional surgical approach includes urethral and genital reconstruction in the first year, followed by bladder neck reconstruction (Young-Dees-Leadbetter cervicoplasty (YDL)) at the age of social continence. An alternative single-stage technique includes urethral, bladder neck and clitoris repair by a perineal approach. The aim of the present study was to describe long-term follow-up of patients who underwent the traditional vs alternative approach. Materials and methods A retrospective review was performed of all female epispadias cases managed between 2000 and 2013. The YDL procedure (Group 1) vs single-stage perineal approach (Group 2) cases were followed and compared. Collected variables included: patients' demographics, age at diagnosis and surgery, presence of associated anomalies, clinical presentation, presence of vesicoureteral reflux (VUR), and pre-operative and postoperative continence. Results A total of 12 cases of female epispadias were managed and followed between 2000 and 2013. No major complications occurred in either group. Urinary continence evaluated in seven children showed that none (0/3) and 4/7 (57%) were continent following the initial procedure in Group 1 and Group 2, respectively. All patients in Group 1 failed to achieve continence and required re-intervention. Conclusions Female epispadias could be successfully repaired using a single-stage modified perineal approach that achieved good continence with volitional voiding, good cosmetic results and compared favorably with the ones repaired with the YDL technique. The additional step of performing bladder neck tailoring to achieve a funneling configuration seemed to be useful in improving continence

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

Chromosomal and SRY gene findings by FISH in patients with disorders of sexual development

Objetivo: Los trastornos del desarrollo sexual son un grupo de enfermedades congénitas que afectan la formación normal de los genitales. Dentro los mecanismos fisiopatológicos descritos existen factores genéticos causados por alteraciones cromosómicas o en los genes determinantes en la diferenciación sexual. En este trabajo se analizaron alteraciones cromosómicas y en el gen SRY como posible causa del trastorno. Se realizó cariotipo con bandas G o R y FISH para SRY en linfocitos, tejido gonadal y tejido escrotal. Materiales y métodos: La información clínica de los sujetos de investigación se obtuvo de los informes de los médicos tratantes. En 9 (73%) casos el sexo asignado fue masculino y en 3 (27%) casos fue femenino. 8 de los casos (66%) tuvieron cariotipo 46,XY; 2 casos (17%) 46,XX y en 2 casos (17%) se reportaron mosaicos con presencia de idic(Y). Un solo caso de tejido gonadal mostró mosaicismo debido a la presencia de una línea celular tetraploide. El diagnóstico clínico más frecuente fue de genitales ambiguos en 8 casos (67%). Seguido de hipospadias en 5 casos (41,7%). Conclusiones: Los resultados muestran la importancia de aplicar diferentes pruebas citogenéticas en el diagnóstico y la necesidad del seguimiento de los pacientes por un equipo transdisciplinario para abordar estas condiciones clínicas.Q4Pacientes diagnosticados con trastornos del desarrollo sexualObjective: Disorders of sexual development are a group of congenital diseases that affect the normal formation of genital structures. Within the pathophysiologic mechanisms described, there are genetic factors caused by chromosomal or sex-determining gene alterations. Therefore, chromosomal analysis is an essential priority in the diagnostic approach. Alterations in the chromosomes and the SRY gene as a cause of disorder of sexual development was analyzed herein. Material and methods: G or R-banding karyotype and FISH analyses for the SRY gene were performed in lymphocytes, gonadal tissue, and scrotal tissue in twelve cases, three cases, and one case, respectively. The clinical information was obtained from the patients’ medical reports. Results: In 9 (73%) cases, the assigned sex was male, and in 3 (27%) cases, it was female. Karyotype 46,XY was found in 8 (66%) cases, 46,XX in 2 (17%) cases, and mosaic karyotype in 2 (17%) cases with idic(Y). A single case of gonadal tissue showed mosaicism due to the presence of a tetraploid cell line. The most common clinical diagnosis was abnormal genital differentiation in 8 (67%) cases, followed by hypospadias in 5 (41.7%) cases. Conclusions: The results show the importance of applying different cytogenetic tests in making the diagnosis, and the need for a multidisciplinary team to address the disorder.https://orcid.org/0000-0001-7501-7307https://orcid.org/0000-0002-0729-6866https://orcid.org/0000-0002-1421-3619https://orcid.org/0000-0001-6336-5347https://orcid.org/0000-0001-8528-4433https://orcid.org/0000-0002-2231-4321https://orcid.org/0000-0002-7856-7213https://orcid.org/0000-0003-2241-7854https://orcid.org/0000-0002-9675-5963https://orcid.org/0000-0001-5685-8354https://orcid.org/0000-0002-0826-6191Revista Internacional - IndexadaCN

Disruptores endócrinos e metabólicos e desordens reprodutivas: perspectivas futuras

There is increasing evidence of the relation between environmental exposures [mainly to endocrine disrupting chemicals (EDC)] and human health impairment. These compounds include a wide assortment of chemicals used in agriculture (organophosphate and organochlorine compounds, fungicides, etc.) and industrial and commercial applications (bisphenol A, phthalates, perfluorinated compounds, etc.). Currently, the main research areas into this relation are related to neurodevelopmental disorders or cancer, and hormonal, metabolic or reproductive disorders or diseases. The incidence rates of metabolic disorders or conditions–obesity, metabolic syndrome or diabetes–and reproductive or infertility problems are on the rise in human populations. However, the already known risk factors do not fully explain the documented trends for these disorders and diseases. In general, it would be highly advisable to increase the number of epidemiological studies in humans and of mechanistic studies in preclinical and/or cellular models to better understand the links between environmental exposure to EDCs and metabolic disorders or conditions such as obesity, metabolic syndrome, diabetes or infertility, including epigenetic aspects as well.Es evidente la importancia que está adquiriendo la asociación entre exposiciones medioambientales (principalmente compuestos alteradores endocrinos) y la afectación de la salud humana. Estos compuestos incluyen una gran variedad de sustancias químicas, tanto de uso hortofrutícola (compuestos organoclorados y organofosforados, fungicidas, etc.), como industrial o comercial (bisfenol A, ftalatos, compuestos perfluorados, etc.). Actualmente, las principales líneas de investigación incluyen los desórdenes en el neurodesarrollo o el cáncer, junto con alteraciones o enfermedades hormonales, metabólicas o reproductivas. La incidencia de desórdenes metabólicos como la obesidad, el síndrome metabólico o la diabetes, y los problemas reproductivos o de infertilidad están incrementándose en poblaciones humanas. No obstante, los factores de riesgo establecidos no pueden explicar completamente las tendencias observadas para estos desórdenes. En general, sería extremadamente recomendable aumentar el número de estudios epidemiológicos en humanos y mecanísticos en modelos preclínicos o celulares que exploren las asociaciones entre exposición a alteradores endocrinos y desórdenes o enfermedades metabólicas como la obesidad, el síndrome metabólico, la diabetes o la infertilidad, incluyendo aspectos epigenéticos.É evidente a importância que tem sido dada à associação entre exposições ambientais (principalmente compostos disruptores endócrinos) e os efeitos na saúde humana. Estes compostos incluem uma variedade de produtos químicos, tanto para uso hortícola (organoclorados e organofosforados, fungicidas, etc.), como no uso industrial e/ou comercial (bisfenol A, ftalatos, compostos perfluorados, etc.). Atualmente, as principais linhas de investigação procuram desordens do desenvolvimento neurológico ou cancro, bem como as alterações hormonais ou doenças associadas à disfunção hormonal, metabólica ou reprodutiva. A incidência de distúrbios metabólicos, como obesidade, síndrome metabólica ou diabetes, e problemas reprodutivos ou infertilidade estão a aumentar em populações humanas. No entanto, os fatores de risco estabelecidos não conseguem explicar totalmente as tendências observadas nestas desordens. Em geral, seria altamente aconselhável aumentar o número de estudos epidemiológicos em humanos e modelos mecanísticos em pré-clínica e/ou celular, para explorar as associações entre a exposição aos disruptores endócrinos e distúrbios ou doenças metabólicas, tais como obesidade, síndrome metabólica, diabetes e infertilidade, incluindo aspetos epigenéticos

LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures

For the Library of Integrated Network-based Cellular Signatures (LINCS) project many gene expression signatures using the L1000 technology have been produced. The L1000 technology is a cost-effective method to profile gene expression in large scale. LINCS Canvas Browser (LCB) is an interactive HTML5 web-based software application that facilitates querying, browsing and interrogating many of the currently available LINCS L1000 data. LCB implements two compacted layered canvases, one to visualize clustered L1000 expression data, and the other to display enrichment analysis results using 30 different gene set libraries. Clicking on an experimental condition highlights gene-sets enriched for the differentially expressed genes from the selected experiment. A search interface allows users to input gene lists and query them against over 100 000 conditions to find the top matching experiments. The tool integrates many resources for an unprecedented potential for new discoveries in systems biology and systems pharmacology. The LCB application is available at http://www.maayanlab.net/LINCS/LCB. Customized versions will be made part of the http://lincscloud.org and http://lincs.hms.harvard.edu websites

Large urachal adenocarcinoma. Case report and literature review

Introducción: Los adenocarcinomas originados en el uraco son entidades poco frecuentes; representan un reto diagnóstico ya que, por su histología, no es fácil diferenciarlos de los adenocarcinomas originados en el colon. Además, no existe un consenso sobre cuál es el mejor manejo médico o quirúrgico. El presente es el reporte del caso de un paciente que cursa con un adenocarcinoma uracal de vejiga mal diferenciado, de tipo intestinal en un hombre de 65 años, previamente asintomático a pesar de ser un tumor de gran tamaño, así como del abordaje diagnóstico y terapéutico empleado. Caso clínico: Se trata de un paciente de 65 años que presenta un cuadro de dolor abdominal intenso secundario a una caída desde su propia altura, por lo que se realiza una TAC de abdomen y pelvis que muestra una masa quística de gran tamaño, que desplaza el colon sigmoide y es aparentemente dependiente de la vejiga. No hay evidencia de adenopatías o compromiso de otros órganos. Se toma una TAC de tórax que descarta lesiones metastásicas en el tórax. Los marcadores tumorales muestran el ACE y el CA125 elevados. Es llevado a laparotomía exploratoria, donde se observa una gran masa dependiente del domo de la vejiga, de bordes lisos y bien definidos, sin compromiso de estructuras vecinas. Se realiza cistectomía parcial y se reseca la masa en su totalidad. El reporte de patología evidencia un adenocarcinoma uracal de vejiga de tipo intestinal. Discusión: El diagnóstico definitivo del adenocarcinoma de uraco es un reto, ya que por su origen embrionario, presenta positividad para marcadores colónicos; así mismo, su histología puede ser similar al adenocarcinoma de colon. Los marcadores histopatológicos son una herramienta fundamental en el diagnóstico definitivo, ya que permiten diferenciarlo del primario en el colon. En la actualidad no existe un consenso sobre el mejor manejo quirúrgico o médico para la enfermedad. Algunos autores proponen la cistectomía parcial como un método seguro en estados bajos de la enfermedad y reservan la cistectomía radical para estadios más avanzados. Conclusión: Es llamativo el curso clínico benigno y asintomático en el paciente, a pesar de tener un tumor de gran tamaño. Según nuestra revisión no hay tumores reportados de este tamaño. En este caso nos basamos en los marcadores histopatológicos para determinar el origen uracal del tumor. Consideramos que no hay elementos que sugieran un mal pronóstico o una alta probabilidad de recurrencia tumoral, por lo que se decidió manejar con cistectomía parcial. La evidencia al respecto es limitada. Debe hacerse un seguimiento clínico en el tiempo para vigilar la presencia de recaídas locales o sistémicas.Q4Introduction: Adenocarcinomas originating in the urachus are rare. They represent a diagnostic challenge. Their histology is very similar to adenocarcinomas that originate in the intestine, making it difficult to differentiate them. Furthermore, there is no consensus on whether surgical or medical management is better. The case is reported on a 65 year-old patient diagnosed with a poorly differentiated, intestinal type, urachal adenocarcinoma of the bladder that was previously asymptomatic despite its large size. A discussion is presented on the diagnostic and therapeutic approach that was used. Clinical case: This is the case of a 65-year-old patient, who complained of intense abdominal pain following a fall from his own height. An abdomen and pelvis computed tomography scan was performed that showed a large-sized cystic mass that displaced the sigmoid colon and was apparently dependent of the dome of the bladder. There was no evidence of lymphadenopathy or of compromise of other organs. A chest computed tomography ruled out metastatic lesions. Tumour markers show elevated CEA and CA125. An exploratory laparotomy was performed, in which a large mass, dependent of the bladder dome was found. It had clean and well-defined edges, without compromise of the neighbouring structures. A partial cystectomy with full resection of the mass was performed. The pathology report showed an intestinal-type urachal adenocarcinoma of the bladder. Discussion: The definitive diagnosis of a urachal adenocarcinoma is a challenge, since, due to its embryonic origin, colon cancer markers are positive. Also, its histology may be similar to an adenocarcinoma of the colon. The histological markers are a fundamental tool for the definitive diagnosis, as they allow the physician to differentiate between a urachal adenocarcinoma and an adenocarcinoma that primarily originated in the colon. There is currently no consensus on the best surgical or medical management of this condition. Some authors propose partial cystectomy as a safe method for low stages of the disease, and reserve the radical cystectomy for more advanced stages. Conclusion: The benign and asymptomatic course of the disease in the patient, despite the large size of the tumour. According to our review, there are no tumours of this size reported in the literature. In this case, we used the histopathological markers to determine the urachal origin of the tumour. As there appeared to be no clinical elements that suggest a poor prognosis or a high probability of tumour recurrence, it was decided to perform a partial cystectomy. The evidence on its management is limited. An appropriate clinical follow-up is necessary in order to check for local or systemic recurrences.https://orcid.org/0000-0002-9675-5963https://orcid.org/0000-0002-3564-6763N/

DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease

A Comprehensive Review

Funding: This project has received funding from the European Unions’ Horizon 2020 research and innovation Programme under grant agreement No 733032. HBM4EU.Polycyclic aromatic hydrocarbons (PAHs) are among the chemicals with proven impact on workers' health. The use of human biomonitoring (HBM) to assess occupational exposure to PAHs has become more common in recent years, but the data generated need an overall view to make them more usable by regulators and policymakers. This comprehensive review, developed under the Human Biomonitoring for Europe (HBM4EU) Initiative, was based on the literature available from 2008-2022, aiming to present and discuss the information on occupational exposure to PAHs, in order to identify the strengths and limitations of exposure and effect biomarkers and the knowledge needs for regulation in the workplace. The most frequently used exposure biomarker is urinary 1-hydroxypyrene (1-OH-PYR), a metabolite of pyrene. As effect biomarkers, those based on the measurement of oxidative stress (urinary 8-oxo-dG adducts) and genotoxicity (blood DNA strand-breaks) are the most common. Overall, a need to advance new harmonized approaches both in data and sample collection and in the use of appropriate biomarkers in occupational studies to obtain reliable and comparable data on PAH exposure in different industrial sectors, was noted. Moreover, the use of effect biomarkers can assist to identify work environments or activities of high risk, thus enabling preventive risk mitigation and management measures.publishersversionpublishe